TY  - JOUR
AU  - Botla, Sandeep K
AU  - Savant, Soniya
AU  - Jandaghi, Pouria
AU  - Bauer, Andrea
AU  - Mücke, Oliver
AU  - Moskalev, Evgeny A
AU  - Neoptolemos, John P
AU  - Costello, Eithne
AU  - Greenhalf, William
AU  - Scarpa, Aldo
AU  - Gaida, Matthias M
AU  - Büchler, Markus W
AU  - Strobel, Oliver
AU  - Hackert, Thilo
AU  - Giese, Nathalia A
AU  - Augustin, Hellmut
AU  - Hoheisel, Jörg
TI  - Early Epigenetic Downregulation of microRNA-192 Expression Promotes Pancreatic Cancer Progression.
JO  - Cancer research
VL  - 76
IS  - 14
SN  - 1538-7445
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2017-01672
SP  - 4149 - 4159
PY  - 2016
AB  - Pancreatic ductal adenocarcinoma (PDAC) is characterized by very early metastasis, suggesting the hypothesis that metastasis-associated changes may occur prior to actual tumor formation. In this study, we identified miR-192 as an epigenetically regulated suppressor gene with predictive value in this disease. miR-192 was downregulated by promoter methylation in both PDAC and chronic pancreatitis, the latter of which is a major risk factor for the development of PDAC. Functional studies in vitro and in vivo in mouse models of PDAC showed that overexpression of miR-192 was sufficient to reduce cell proliferation and invasion. Mechanistic analyses correlated changes in miR-192 promoter methylation and expression with epithelial-mesenchymal transition. Cell proliferation and invasion were linked to altered expression of the miR-192 target gene SERPINE1 that is encoding the protein plasminogen activator inhibitor-1 (PAI-1), an established regulator of these properties in PDAC cells. Notably, our data suggested that invasive capacity was altered even before neoplastic transformation occurred, as triggered by miR-192 downregulation. Overall, our results highlighted a role for miR-192 in explaining the early metastatic behavior of PDAC and suggested its relevance as a target to develop for early diagnostics and therapy. Cancer Res; 76(14); 4149-59. ©2016 AACR.
KW  - Cadherins (NLM Chemicals)
KW  - MIRN192 microRNA, human (NLM Chemicals)
KW  - MicroRNAs (NLM Chemicals)
KW  - Plasminogen Activator Inhibitor 1 (NLM Chemicals)
KW  - SERPINE1 protein, human (NLM Chemicals)
KW  - Vimentin (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27216198
DO  - DOI:10.1158/0008-5472.CAN-15-0390
UR  - https://inrepo02.dkfz.de/record/125546
ER  -